Antimetabolites have been used for a number of years as chemotherapeutic agents in the treatment of cancer. One such drug, methotrexate, is now one of the most widely used anticancer drugs; and many other compounds in the folic acid family have been synthesized, tested and discussed in the chemical and medical literature. The compounds have various activities at the enzymatic level; they inhibit such enzymes as dihydrofolate reductase, folate polyglutamate synthetase, glycinamide ribonucleotide formyltransferase and thymidylate synthetase.
More recently, a series of 4-hydroxypyrrolo[2,3-d]pyrimidine-L-glutamic acid derivatives have been disclosed and shown to be particularly useful antifolate drugs. See, for example, U.S. Pat. Nos. 4,996,206; 5,106,974; and 4,997,838. However, the synthetic pathways described therein greatly vary and are frequently inconvenient and complex.
The present invention provides an improved process for the synthesis of intermediates which are useful for the synthesis of 4-hydroxypyrrolo[2,3-d]pyrimidine based antifolate compounds. The process of the present invention is also useful for the synthesis of antifolate compounds which are employed as antineoplastic agents.
Although the intermediate compounds synthesized by the process of this invention are primarily useful for the synthesis of antineoplastic glutamic acid derivatives, one of ordinary skill in the pharmaceutical and organic chemical arts will recognize that the usefulness of these intermediates is not limited to the synthesis of the abovedescribed antineoplastic agents.